Mycobacterium tuberculosis (M.tb) is the causative agent of pulmonary tuberculosis (TB). Over 25% of the world’s population is estimated to be infected with tuberculosis, yielding over 10 million new cases and over 1.5 million deaths in 2017 alone. This is all despite the near universal implementation of bacille Calmette-Guérin (BCG) vaccination across TB endemic areas. BCG is capable of preventing childhood disseminated forms of disease but fails to induce potent immunity within the lung. We expect this to in part play a role in the lack of protection against pulmonary TB. Our lab has developed a human adenovirus serotype 5 vaccine expressing the M.tb antigen Ag85A (AdHu5Ag85A). When delivered directly to the respiratory mucosa (RM), AdHu5Ag85A has proven to be safe and immunogenic, generating both CD4 and CD8 T cell responses within the lung. We have found that RM AdHu5Ag85A vaccination also generates a long-lasting population of memory macrophages in the airway and lung, that are primed to better control early M.tb infection. Importantly, this was a vaccination route-dependent mechanism. Memory macrophages express a trained innate immune phenotype as they express high levels of MHC II, are highly glycolytic, and produce more IL-12 upon re-stimulation. Importantly, utilization of an in vivo T cell depletion approach allowed us to show that these memory macrophages are capable of limiting early M.tb infection independent of T cells. Our findings indicate that RM vaccination may be advantageous to parenteral routes by not only drawing antigen specific T cells into immunologically restricted lung mucosa but also generating a memory macrophage population within the lung. Induction of memory macrophages within the airway helps overcome early innate immune suppression by M.tb. / Thesis / Master of Health Sciences (MSc) / Tuberculosis (TB) is a pulmonary disease responsible for 10 million new clinical cases and more than 1 million deaths annually. Over one quarter of the world is believed to be infected with TB. This is despite the near-universal administration of bacille Calmette-Guérin, a preventative TB vaccine, and an effective, but lengthy antibiotic treatment. With antibiotic resistance on the rise, developing a protective vaccine against TB is more important than ever. Tuberculosis has confounded researchers for decades and has thus escaped development of a more effective vaccine. One of the ways to improve a TB vaccine would be to inhale it, to have local effects at the main site of TB infection in the lung. We found that by aerosolizing our vaccine, we can impact local immunity within the lung in a way that has never before been described, opening new avenues for TB research.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/24846 |
| Date | January 2019 |
| Creators | D'Agostino, Michael |
| Contributors | Xing, Zhou, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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